Several human diseases appear to result from the epistatic interaction of two genetic loci. There exist, however, only limited ways of testing whether an inherited disease in the result of two (or more) loci. The recent report of methods testing whether disease results from two epistatically interacting loci, and their application to coeliac disease, was an attempt to provide and apply such methodology. However, the methods are ad hoc and the limits of their applicability are unknown. I propose to test and define these methods for testing two-locus models of inheritance. This will be accomplished by simulating data assuming different values of the possible parameters (e.g. gene frequency, "actual" mode of inheritance (as defined by the simulation), ascertainment conditions, etc.) and testing how well the different models of two-locus inheritance are distinguished from each other, from single-locus models, and from models involving more than two loci. In addition to developing the two-locus methods, I propose to examine insulin dependent diabetes mellitus (IDDM) as a two-locus disease. The evidence that IDDM results from the interaction of two loci, in addition to environmental factors, has been steadily accumulating. Two other factors making IDDM attractive for examining as a two-locus disease are that there is evidence for both the mode of inheritance at the HLA-associated locus and for the heterogeneity of the disease.